Human sporadic breast carcinomas are characterized by the presence of complex cytogenetic aberrations. This complexity represents one of the foremost challenges for breast cancer researchers developing the experimental model systems to identify the molecular genetic etiology of breast tumor development. Our long term goal is to establish chromosomal instability mouse breast cancer models that recapitulate the salient features of highly rearranged and mutated human breast cancer genomes and discover the causal genomic events involved in mammary carcinogenesis in vivo. One important mechanism that can give rise to the unstable genome in breast cancer is the dysfunction of telomeres, the physical termini of chromosomes that protect natural chromosomal ends from being recognized as damaged DNA and inhibit inappropriate DNA repair. On the other hand, recent systematic genomic analyses in human breast carcinomas have revealed that tumor suppressor p53 is the most commonly alerted gene, predominantly through missense mutations that result in accumulation of mutant p53 protein to acquire oncogenic gain-of-function. To faithfully resemble these two important features observed in human breast carcinomas, chromosomal instability and expression of gain- of-function mutant p53, we have been engineering a novel mouse breast cancer model bearing dysfunctional telomere-induced chromosomal instability and expression of hot spot gain-of-function mutant p53 in breast epithelium. Our preliminary results suggest that telomere uncapping causes dysfunctional telomeres that activate DNA Damage Response (DDR)-mediated apoptotic pathway to suppress chromosomal instability- driven tumorigenesis in the absence of p53, while hot spot mutant p53 inhibits telomere uncapping-induced cell death and promotes cell transformation. Furthermore, we observe that mutant p53 cooperates with dysfunctional telomeres in breast epithelium to promote tumor progression to invasive breast carcinomas in vivo. In this application, we will test our hypothesis that gain-of-function mutant p53 inhibits telomere uncapping-induced DDR-mediated apoptosis to enhance chromosomal instability-driven mammary carcinogenesis in vivo. The two specific aims are designed to test the hypothesis. In Aim 1, we will generate mouse models to test the possibility that gain-of-function mutant p53 cooperates with telomere uncapping- initiated chromosomal instability to promote mammary carcinogenesis in vivo. In Aim 2, we will investigate the molecular mechanism underlying gain-of-function mutant p53 promotes chromosomal instability-driven breast tumor development. We anticipate that our engineered chromosomal instability mouse models will faithfully recapitulate the complex cytogenetic aberrations of human breast cancer and help us identify novel molecular targets to improve strategies for the prevention and treatment of breast cancer.